Mutant prion protein impairs delivery of voltage gated calcium channels to the presynaptic membrane: mechanisms of neurotoxicity and potential therapeutic strategies

Prion diseases, including Creutzfeldt-Jakob disease, Gerstmann-Sträussler Scheinker syndrome, fatal familial insomnia and kuru in humans, mad cow disease (BSE), and scrapie in sheep, are fatal neurodegenerative disorders arising from the conformational conversion of a single normal protein of the brain (prion protein, PrP) to an altered disease-causing form. This altered form of PrP accumulates in the brains of the patients and causes abnormal proliferation of certain cells of the brain (gliosis), holes in the brain tissue (spongiosis), and loss of neurons (neurodegeneration), leading to dementia and motor dysfunction. Prion diseases can be sporadic, infectious or inherited. Inherited prion diseases are due to mutations in the PrP gene, which are believed to alter the structure of PrP and favor its conversion to the disease-specific species. The aim of the present study is to explore the hypothesis that mutant PrP causes disease by altering specific molecular mechanisms that govern nervous transmission. This hypothesis is based on our recent finding that mutant PrP inhibits the insertion of voltage gated calcium channels at the cell surface, a process which damages the release of the chemical messenger glutamate from the nerve endings (synapses). We aim now at discovering how this altered process causes neuronal death. To this purpose, we will use an array of up-to-date biochemical, electrophysiological and morphological methods, and established transgenic mouse models of inherited prion disease. Similarly to humans, these mice exhibit a slowly progressive neurological disorder characterized by ataxia and cerebellar atrophy, and therefore represent a suitable model for studying the biological mechanisms underlying inherited prion diseases. By identifying the primary dysfunctions occurring in the presymptomatic stage of the disease, we hope to contribute to establishing the rationale for developing an effective therapy for these devastating disorders.